Selection Pressures in the Aged Microenvironment Drive Transformation of Dnmt3a-Mutant Hematopoietic Stem Cells to Myeloid Malignancy

Driver somatic mutations in adult acute myeloid leukemia (AML) are often preceded by a benign or premalignant state termed clonal hematopoiesis (CH) for which the greatest risk factor is aging. To risk-stratify aged individuals and develop therapies to prevent AML, we need to understand the variables that promote transformation from CH to AML. Using our orthogonally inducible Dnmt3aR878H;Npm1cA-mutant model of progression from CH to myeloid malignancy, we find that in young mice, Dnmt3a mutation buffers against myeloid differentiation, proliferation, acquisition of cooperating mutations and transformation induced by stress, inflammation, and the oncogenic Npm1 mutation. However, when Dnmt3a;Npm1-mutant hematopoietic stem cells (HSCs) are transplanted into naturally aged recipient mice, they gain myeloid-biased differentiation capacity and have an accelerated transformation to AML. These results support the hypothesis that alterations in the aged microenvironment drive risk of AML in individuals with CH and help to explain why this Dnmt3a mutation is exceedingly rare in pediatric leukemias. Overall design: 4 control and 3 mutant LTHSC, 3 control 4 mutant STHSC, 3 control and 3 mutant MPP3, 4 mutant and 4 control MPP4 from young 6 week post PIPC mice.